Mitochondrial genes

SIGNIFICANCE:Mutations in mitochondrial genes have been shown to cause several human genetic diseases associated with a gradual loss of tissue function. Understanding the functions of mitochondrial genes and their nuclear counterparts may lead to the development of treatments for these debilitating diseases. Analysis of the mitochondrial DNA sequence of different human populations has also provided information relevant to the understanding of human evolution.

Mitochondrial Structure and Function

Mitochondria are membrane-bound organelles that exist in the cytoplasm of eukaryotic cells. Structurally, they consist of an outer membrane and a highly folded inner membrane that separate the mitochondria into several compartments. Between the two membranes is the intermembrane space; the innermost compartment bounded by the inner membrane is referred to as the matrix. In addition to enzymes involved in glucose metabolism, the matrix contains several copies of the mitochondrial chromosome as well as ribosomes, transfer RNA (tRNA), and all the other factors required for protein synthesis. Mitochondrial ribosomes are structurally different from the ribosomes located in the cytoplasm of the eukaryotic cell and, in fact, more closely resemble ribosomes from bacterial cells. This similarity led to the endosymbiont hypothesis developed by Lynn Margulis, which proposes that mitochondria arose from bacteria that took up residence in the cytoplasm of the ancestor to eukaryotes.

Embedded in the inner mitochondrial membrane is a series of protein complexes that are known collectively as the electron transport chain. These proteins participate in a defined series of reactions that begin when energy is released from the breakdown of glucose and end when oxygen combines with 2H⁺ ions to produce water. The net result of these reactions is the movement of H⁺ ions (also called protons) from the matrix into the intermembrane space. This establishes a proton gradient in which the intermembrane space has a more positive charge and is more acidic than the matrix. Thus mitochondria act as tiny batteries that separate positive and negative charges in order to store energy. Another protein that is embedded in the inner mitochondrial membrane is an called adenosine triphosphate (ATP) synthase. This enzyme allows the H⁺ ions to travel back into the matrix. When this happens, energy is released that is then used by the synthase enzyme to make ATP. Cells use ATP to provide energy for all of the biological work they perform, including movement and synthesis of other molecules. The concept of linking the production of a proton gradient to ATP synthesis was developed by Peter Mitchell in 1976 and is referred to as the chemiosmotic hypothesis.

Mitochondrial Genes

The mitochondrial chromosome is a circular DNA molecule that varies in size from about 16,000 base pairs (bp) in humans to more than 100,000 base pairs in certain species of plants. Despite these size differences, mitochondrial DNA (mtDNA) contains only a few genes that tend to be similar over a wide range of organisms. This discussion will focus on genes located on the human mitochondrial chromosome that has been completely sequenced. These genes fall into two broad categories: those that play a role in mitochondrial protein synthesis and those involved in electron transport and ATP synthesis.

Mitochondria have their own set of ribosomes that consist of a large and a small subunit. Each ribosomal subunit is a complex of and proteins. Genes that play a role in mitochondrial protein synthesis include two genes designated MT-RNR2 (16S rRNA) and MT-RNR1 (12S rRNA), indicating the RNA for the large and small subunits respectively. Also in this first category are genes for mitochondrial transfer RNA. Transfer RNA (tRNA) is an L-shaped molecule that contains the RNA at one end and an amino acid attached to the other end. The anticodon pairs with the of the and brings the correct amino acid into position to be added to the growing protein chain. Thus the tRNA molecule serves as a bridge between the information in the molecule and the sequence of amino acids in the protein. Mitochondrial tRNAs are different from those involved in protein synthesis in the cytoplasm. In fact, cytoplasmic tRNAs would not be able to function on mitochondrial ribosomes, nor could mitochondrial tRNAs work with cytoplasmic ribosomes. Thus, contains a complete set of twenty-two tRNA genes.

Genes involved in electron transport fall into the second category of mitochondrial genes. The is divided into a series of protein complexes, each of which consists of a number of different proteins, a few of which are encoded by mtDNA. The NADH dehydrogenase complex (called complex I) contains about twenty-two different proteins. In humans, only six of these proteins are encoded by genes located on the mitochondrial chromosome. Cytochrome c reductase (complex III) contains about nine proteins, including cytochrome b, which is the only one whose gene is located on mtDNA. Cytochrome oxidase (complex IV) contains seven proteins, three of which are encoded by mitochondrial genes. About sixteen different proteins combine to make up the mitochondrial ATP synthase, and only two of these are encoded by mtDNA.

All of the proteins not encoded by mitochondrial genes are encoded by genes located on nuclear chromosomes. In fact, more than 90 percent of the proteins found in the mitochondria are encoded by nuclear genes. These genes must be transcribed into mRNA in the nucleus, then the mRNA must be translated into protein on cytoplasmic ribosomes. Finally, the proteins are transported into the mitochondria where they function. By contrast, genes located on mtDNA are transcribed in the mitochondria and translated on mitochondrial ribosomes.

Impact and Applications

Any mutation occurring in a mitochondrial gene has the potential to reduce or prevent mitochondrial ATP synthesis. Because human cells are dependent upon mitochondria for their energy supply, the effects of these mutations can be wide-ranging and debilitating, if not fatal. If the mutation occurs in a gene that plays a role in mitochondrial protein synthesis, the ability of the mitochondria to perform protein synthesis is affected. Consequently, proteins that are translated on mitochondrial ribosomes such as cytochrome b or the NADH dehydrogenase subunits cannot be made, leading to defects in electron transport and ATP synthesis. Mutations in mitochondrial tRNA genes, for example, have been shown to be the cause of several degenerative neuromuscular disorders. Genes involved in electron transport and ATP synthesis have a more directly negative effect when mutated. Douglas C. Wallace and coworkers identified a mutation within the NADH dehydrogenase subunit 4 gene, for example, that was the cause of a maternally inherited form of blindness and was one of the first mitochondrial diseases to be identified. According to Jonathan Max Gitlin for the National Human Genome Research Institute in 2012, mitochondrial dysfunction is seen in about four thousand newborns in the United States each year. Gitlin also notes that while researchers have identified seventy-seven genes known to cause mitochondrial diseases, the gene or genes causing the dysfunction remain unidentified in half of all cases.

Of further interest is the study of nuclear genes that contribute to mitochondrial function. Included in this list of nuclear genes are those encoding proteins involved in mtDNA replication, repair, and recombination; enzymes involved in RNA transcription and processing; and ribosomal proteins and the accessory factors required for translation. It is presumed that a mutation in any of these genes could have negative effects upon the ability of the mitochondria to function. Understanding how nuclear genes contribute to mitochondrial activity is an essential part of the search for effective treatments for mitochondrial diseases.

Human evolutionary studies have also been affected by the understanding of mitochondrial genes and their inheritance. Researchers Allan C. Wilson and Rebecca Cann, knowing that mitochondria are inherited exclusively through the female parent, hypothesized that a comparison of mitochondrial DNA sequences in several human populations would enable them to trace the origins of the ancestral human population. These studies led to the conclusion that a female living in Africa about 200,000 years ago was the common ancestor for all humans; she is referred to as “mitochondrial Eve.”

Key Terms

• adenosine triphosphate (ATP)the molecule that serves as the major source of energy for the cell
• ATP synthasethe enzyme that synthesizes ATP
• cytochromesproteins found in the electron transport chain
• electron transport chaina series of protein complexes that pump H⁺ ions out of the mitochondria as a way of storing energy that is then used by ATP synthase to make ATP
• mitochondrial DNA (mtDNA)genetic material found uniquely in mitochondria, located outside the nucleus and therefore separate from the nuclear DNA
• ribosomesorganelles that function in protein synthesis and are made up of a large and a small subunit composed of proteins and ribosomal RNA (rRNA) molecules
• spacerslong segments of DNA rich in adenine-thymine (A-T) base pairs that separate exons and introns, although most of the spacer DNA is transcribed but is not translated messenger RNA (mRNA)

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